Functional changes in both adaptive and innate immunity contribute to immunosenescence during aging. The immune system has also been implicated in inflammation, autoimmunity and reduced protein aggregate clearance in the brains of patients with Alzheimer?s disease (AD). Aging immune cells harbor wide-ranging impairment of autophagy pathways, including macroautophagy (MA) and chaperone-mediated autophagy (CMA), which trigger functional alterations in key immune cell subsets, such as T cells and monocyte-derived macrophages. Mechanisms responsible for the aging-associated decrease in autophagic activity and a comprehensive characterization of their functional consequences has remained elusive, but may hold the key for the development of innovative new therapies to counteract aging-associated neurodegenerative processes and pathologies, including AD and AD related dementias. In previous periods of this PP, we have identified new and specific functions of autophagy in the immune system and have characterized aging-associated dysregulation of MA and CMA in immune cells. This acquired knowledge, established tools and gained expertise allows us to now work towards a better understanding of new important concepts in the context of Geroscience ? specifically, to define how an altered interplay between two organ systems, the immune system and the central nervous system, facilitates propagation of dysregulated autophagy-mediated proteostasis networks and leads to age-associated pathologies. In this project, we will investigate the functional consequences of an aging hematopoietic and peripheral immune system with impaired proteostasis in AD, as well as characterize the reciprocal effects of AD on immune cell generation and function. We will determine the consequences of altered proteostasis in T cells in the development and progress of Alzheimer?s disease (Aim1), characterize the role of age-associated autophagy- defective innate immune cells originating from commonly occurring acquired clonal hematopoiesis in neurodegeneration and AD during aging (Aim2) and elucidate how AD-associated proteotoxicity contributes to the dysregulation of function and proteostasis in the bone marrow and peripheral immune cells (Aim3), Integration in the PP: This project will utilize novel CMA reporter mice, develop new mouse models with modulated autophagy in T cells to assess the consequences of improve proteostasis in T cells for AD pathology, and establish and test novel AD mouse models harboring autophagy-impaired innate immune cells originating form age-associated clonal hematopoiesis. We will also use the three experimental mouse models of AD. All mice will be maintained by the Animal Core and shared by all the projects. Importantly, we will utilize chemical modulators of CMA developed by Therapeutics Core to evaluate their ability to restore immune function and inhibit or slow progress of neurodegeneration and AD pathology. Image-based analysis of the changes in peripheral and central autophagy and assessment of in vivo immune cell function will be done with state-of-the- art image technology provided by the Image Core. Mechanisms of intercommunication between peripheral and central autophagy will be investigated in conjunction with P1 and P4, and the ability of brain-draining lymph carried products to influence immune cell function will be studied together with P2. The Biostatistics Unit will assist with analysis of data and integration of results from all four projects. Relevance to public health: Our study will identify mechanisms triggering altered hematopoiesis and peripheral immune function in the elderly and provide novel fundamental insights into the systemic relationships of tissue degeneration during aging. Moreover, the data collected herein are very likely to provide strong preclinical rationales for developing novel therapeutic interventions for age-associated pathologies by restoring autophagy.